Enantiomerically Enriched α-Methyl Amino Acids. Use of an Acyclic, Chiral Alanine-Derived Dianion with a High Diastereofacial Bias

David B Berkowitz, Marianne K. Smith

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Hindered esters derived from N-benzoylalanine and the following chiral alcohols have been synthesized: (1) (-)-isopinocampheol, (2) (-)trans-2-phenylcyclohexanol, and (3) (-)-8-phenylmenthol. Sequential treatment of these esters with LDA (1.2 equiv) and n-butyllithium (2.4 equiv) at-78 C in THF generates the corresponding chiral dianions. Alkylation of each of these with benzyl bromide reveals that only the (-)-8-phenylmenthyl auxiliary confers a high diastereofacial bias upon its derivative dianion. In fact, that dianion (6) consistently displays diastereomeric ratios in the range of 89:11 to 94:6 for alkylations with a spectrum of nine alkyl halides. If one recrystallization step is included, a single diastereomeric product may be obtained, as is demonstrated for the benzylation of 6. Of particular note, the alkylation with 3, 4-bis((tert-butyldimethylsilyl) oxy)benzyl bromide (18) (94:6 diasteriomeric ratio, 72% yield) constitutes a formal synthesis of the clinically important antihypertensive (S)-α-methyl-DOPA (Aldomet), in enantiomerically enriched form. In all cases studied, yields are markedly improved, yet diastereoselectivities unchanged, by the addition of 10% HMPA to the reaction milieu. The (-)-8-phenylmenthol chiral auxiliary is conveniently recovered via ester cleavage with KO2/18-crown-6, following alkylation. Complete deprotection affords enantiomerically enriched (S)-α-methyl amino acids, in all cases examined, indicating that dianion 6 displays a substantial bias in favor of si face alkylation. This sense of diastereoselection is consistent with a chain-extended, internal chelate model for the reactive conformation of the dianion.

Original languageEnglish (US)
Pages (from-to)1233-1238
Number of pages6
JournalJournal of Organic Chemistry
Volume60
Issue number5
DOIs
StatePublished - Mar 1 1995

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Alkylation
Alanine
Amino Acids
Esters
Hempa
Methyldopa
Antihypertensive Agents
Conformations
Alcohols
Derivatives
8-phenylmenthol
benzyl bromide

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Enantiomerically Enriched α-Methyl Amino Acids. Use of an Acyclic, Chiral Alanine-Derived Dianion with a High Diastereofacial Bias. / Berkowitz, David B; Smith, Marianne K.

In: Journal of Organic Chemistry, Vol. 60, No. 5, 01.03.1995, p. 1233-1238.

Research output: Contribution to journalArticle

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abstract = "Hindered esters derived from N-benzoylalanine and the following chiral alcohols have been synthesized: (1) (-)-isopinocampheol, (2) (-)trans-2-phenylcyclohexanol, and (3) (-)-8-phenylmenthol. Sequential treatment of these esters with LDA (1.2 equiv) and n-butyllithium (2.4 equiv) at-78 C in THF generates the corresponding chiral dianions. Alkylation of each of these with benzyl bromide reveals that only the (-)-8-phenylmenthyl auxiliary confers a high diastereofacial bias upon its derivative dianion. In fact, that dianion (6) consistently displays diastereomeric ratios in the range of 89:11 to 94:6 for alkylations with a spectrum of nine alkyl halides. If one recrystallization step is included, a single diastereomeric product may be obtained, as is demonstrated for the benzylation of 6. Of particular note, the alkylation with 3, 4-bis((tert-butyldimethylsilyl) oxy)benzyl bromide (18) (94:6 diasteriomeric ratio, 72{\%} yield) constitutes a formal synthesis of the clinically important antihypertensive (S)-α-methyl-DOPA (Aldomet), in enantiomerically enriched form. In all cases studied, yields are markedly improved, yet diastereoselectivities unchanged, by the addition of 10{\%} HMPA to the reaction milieu. The (-)-8-phenylmenthol chiral auxiliary is conveniently recovered via ester cleavage with KO2/18-crown-6, following alkylation. Complete deprotection affords enantiomerically enriched (S)-α-methyl amino acids, in all cases examined, indicating that dianion 6 displays a substantial bias in favor of si face alkylation. This sense of diastereoselection is consistent with a chain-extended, internal chelate model for the reactive conformation of the dianion.",
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N2 - Hindered esters derived from N-benzoylalanine and the following chiral alcohols have been synthesized: (1) (-)-isopinocampheol, (2) (-)trans-2-phenylcyclohexanol, and (3) (-)-8-phenylmenthol. Sequential treatment of these esters with LDA (1.2 equiv) and n-butyllithium (2.4 equiv) at-78 C in THF generates the corresponding chiral dianions. Alkylation of each of these with benzyl bromide reveals that only the (-)-8-phenylmenthyl auxiliary confers a high diastereofacial bias upon its derivative dianion. In fact, that dianion (6) consistently displays diastereomeric ratios in the range of 89:11 to 94:6 for alkylations with a spectrum of nine alkyl halides. If one recrystallization step is included, a single diastereomeric product may be obtained, as is demonstrated for the benzylation of 6. Of particular note, the alkylation with 3, 4-bis((tert-butyldimethylsilyl) oxy)benzyl bromide (18) (94:6 diasteriomeric ratio, 72% yield) constitutes a formal synthesis of the clinically important antihypertensive (S)-α-methyl-DOPA (Aldomet), in enantiomerically enriched form. In all cases studied, yields are markedly improved, yet diastereoselectivities unchanged, by the addition of 10% HMPA to the reaction milieu. The (-)-8-phenylmenthol chiral auxiliary is conveniently recovered via ester cleavage with KO2/18-crown-6, following alkylation. Complete deprotection affords enantiomerically enriched (S)-α-methyl amino acids, in all cases examined, indicating that dianion 6 displays a substantial bias in favor of si face alkylation. This sense of diastereoselection is consistent with a chain-extended, internal chelate model for the reactive conformation of the dianion.

AB - Hindered esters derived from N-benzoylalanine and the following chiral alcohols have been synthesized: (1) (-)-isopinocampheol, (2) (-)trans-2-phenylcyclohexanol, and (3) (-)-8-phenylmenthol. Sequential treatment of these esters with LDA (1.2 equiv) and n-butyllithium (2.4 equiv) at-78 C in THF generates the corresponding chiral dianions. Alkylation of each of these with benzyl bromide reveals that only the (-)-8-phenylmenthyl auxiliary confers a high diastereofacial bias upon its derivative dianion. In fact, that dianion (6) consistently displays diastereomeric ratios in the range of 89:11 to 94:6 for alkylations with a spectrum of nine alkyl halides. If one recrystallization step is included, a single diastereomeric product may be obtained, as is demonstrated for the benzylation of 6. Of particular note, the alkylation with 3, 4-bis((tert-butyldimethylsilyl) oxy)benzyl bromide (18) (94:6 diasteriomeric ratio, 72% yield) constitutes a formal synthesis of the clinically important antihypertensive (S)-α-methyl-DOPA (Aldomet), in enantiomerically enriched form. In all cases studied, yields are markedly improved, yet diastereoselectivities unchanged, by the addition of 10% HMPA to the reaction milieu. The (-)-8-phenylmenthol chiral auxiliary is conveniently recovered via ester cleavage with KO2/18-crown-6, following alkylation. Complete deprotection affords enantiomerically enriched (S)-α-methyl amino acids, in all cases examined, indicating that dianion 6 displays a substantial bias in favor of si face alkylation. This sense of diastereoselection is consistent with a chain-extended, internal chelate model for the reactive conformation of the dianion.

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